JP2010024181A - Solid preparation and method for producing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a solid preparation with improved disintegradability, and a production method thereof. <P>SOLUTION: The solid preparation comprises an active ingredient (e.g. vitamin B<SB>6</SB>etc.) and carboxy group-containing monosaccharides or a derivative thereof (e.g. glucuronic acid, an amide thereof, glucuronolactone, etc.) and optionally further comprises glycosaminoglycans. Here, the carboxy group-containing monosaccharides or a derivative thereof and the glycosaminoglycans (chondroitin sulfate or a salt thereof) may be contained in grouped forms (i.e. grouped into a preparation group containing vitamin B<SB>6</SB>and carboxy group-containing monosaccharides or a derivative thereof, and a preparation group containing vitamin B<SB>1</SB>, vitamin B<SB>12</SB>and glycosaminoglycans). The solid preparation displays high disintegration without substantially containing any disintegrant. The solid preparation may be a coated tablet. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a solid preparation (such as a vitamin-containing preparation) containing a carboxyl group-containing monosaccharide or a derivative thereof (such as glucuronolactone) and suitable for oral administration, a method for producing the same, and a method for improving the disintegration property of the solid preparation.

  Glucuronic acid is a component such as heparin, chondroitin sulfate, and hyaluronic acid, and its lactone, glucuronolactone, is a component that promotes improvement of liver function and is used as a liver function improving agent. For example, glucuronolactone is a vitamin that is taken as a nutritional supplement for nutritional tonic and physical fatigue in the hope of promoting the function of excretion of “harmful and toxic substances” that cause “fatigue / dullness” to the outside. It is blended in health supplements (vitamin preparations).

  JP 2004-10533 A (Patent Document 1) discloses a cartilage production promoter, a disease derived from cartilage damage (glucuronic acid, a salt thereof, or a glucuronic acid precursor (such as glucuronolactone)) as an active ingredient. For example, a prophylactic or therapeutic agent for arthritis, rheumatism, etc.) or a glycosaminoglucan and / or proteoglucan production promoter is disclosed, and it is further described that a glucosamine salt may be contained as an active ingredient.

On the other hand, various solid preparations have been proposed for the vitamin preparation. For example, Japanese Patent 2002-316930 (Patent Document 2), a (1) vitamin _{B 1} class, and vitamin _{B 1} class of granules granulated and dried using a vitamin _{B 12} analog-containing solvents, (2 ) Tocopherol succinate or a salt thereof and (3) other active ingredients are mixed with a binder, granulated and dried using a vitamin B _12- containing solvent, mixed with other active ingredient granules, Concrete the manufacturing method of the vitamin preparations formulated in tablets, and granules of vitamin B ₁ class which was granulated and dried vitamin B ₁ class with a solvent, the other active ingredient with a vitamin B ₁₂ analog-containing solvents A method of stabilizing vitamin B ₁₂ compounds by mixing granules and other dried active ingredient granules, granulating and drying them is disclosed. However, in this method, since the disintegration property of the solid preparation is low, it is necessary to prepare a preparation containing an excipient. On the other hand, when an excipient is contained, the preparation tends to be large, and the ingestibility cannot be improved.

The JP 2004-26846 (Patent Document 3), a composition containing a vitamin _{B 1} class and glucosamine acids, glucosamine acids with respect to vitamin _{B 1} class 1 part by weight 0.1 - 1000 Disclosed is a composition for treating or preventing arthralgia comprising parts by weight. This document may further contain glycosaminoglycans (such as sodium chondroitin sulfate), glucosamines in a proportion of 10 to 500 parts by weight _per 1 part by weight of vitamin B, vitamins Glycosaminoglycans may be included in a proportion of 30 to 200 parts by weight with respect to 100 parts by weight of the total amount of B ₁ and glucosamine, and further selected from vitamin B ₆ and vitamin B ₁₂ It is described that at least one kind may be included. However, preparations containing glucosamines cannot improve disintegration. Therefore, even in this preparation, a disintegrant is required to improve disintegration. Moreover, even if it shape | molds in the form of a tablet, a crack may arise in a tablet. Note that Patent Document 3 also describes that glucuronolactone, glucuronic acid and the like may be further contained. However, when glucuronolactone or the like is further used in combination, discoloration or coloring occurs, which may reduce storage stability and formulation quality.

In JP-A-9-169651 (Patent Document 4), a granulated granule containing 75 to 97% by weight of vitamin B ₆ is blended with vitamin B ₁ , vitamin B ₁₂ and other active ingredients to produce tablets. A vitamin-containing preparation which is a tablet and the total content of all active ingredients is 65 to 80% by weight in the uncoated tablet is disclosed. This document also describes that vitamin B ₁ , vitamin B ₁₂ and other active ingredients are added as granulated granules, and that the content decreases when vitamin B ₁ and vitamin B ₁₂ coexist. .

Japanese Patent Application Laid-Open No. 2004-256517 (Patent Document 5) contains fursultiamine hydrochloride, sodium chondroitin sulfate and vitamin B ₁₂ (cyanocobalamin, hydroxocobalamin acetate, mecobalamin, etc.) in a plain tablet, On the other hand, a film-coated tablet coated with a film layer containing hydroxypropylmethylcellulose at 8% (w / w) or more is disclosed. In Example 1 of Patent Document 5, a T group sized powder containing fursultiamine hydrochloride, sodium chondroitin sulfate, powdered reduced maltose water candy, cyanocobalamin, and hydroxypropylcellulose, pyridoxine hydrochloride, glucosamine hydrochloride, Obtained Group B sized powder containing powdered reduced maltose water candy and hydroxypropyl cellulose, and mixed the obtained Group T sized powder, Group B sized powder, croscarmellose sodium, magnesium stearate, and mixed The powder was tableted to obtain an uncoated tablet, and this uncoated tablet was coated with a coating solution containing hydroxypropylmethylcellulose, talc 7, titanium oxide, yellow ferric oxide and purified water to obtain a film-coated tablet. It is also described.

However, even in these preparations, a disintegrant is required to improve disintegration. Patent Document 5 also describes that glucuronolactone, glucuronic acid amide and the like may be further contained. However, when glucuronolactone or the like is further used in combination, discoloration or coloring may occur and storage stability may be lowered.
JP 2004-10533 A (claims, effects of the invention) JP 2002-316930 A (Claims, Examples) JP 2004-26846 A (claims, paragraph [0029]) JP-A-9-169651 ((Claims, paragraph [0005]) JP 2004-256517 A (claims, paragraph [0008], Example 1)

  Accordingly, an object of the present invention is to provide a solid preparation (vitamin preparation and the like) having improved disintegration without using a disintegrant and a method for producing the same.

  Another object of the present invention is to provide a solid preparation having no coloration and excellent stability (storage stability) and a method for producing the same.

  Another object of the present invention is to provide a solid preparation (such as a vitamin-containing solid preparation) having improved disintegration and no coloring and excellent stability of an active ingredient, and a method for producing the same.

  Still another object of the present invention is to provide a method capable of improving the disintegration property of a solid preparation (such as a vitamin preparation) without containing a disintegrant.

  As a result of intensive studies to achieve the above-mentioned problems, the present inventors have found that glucosamines reduce the disintegration property of solid preparations, whereas glucuronic acid and its derivatives (amides, salts, lactones, etc.) are added to solid preparations. When used as a carrier, disintegration can be improved without using a disintegrant, and when glucuronic acid and its derivatives are combined with glycosaminoglycans, the disintegration of a solid preparation is further improved without using a disintegrant. In addition, the present inventors have found that coloring can be effectively prevented when a solid preparation is produced in a form that can suppress or prevent direct contact between glucuronic acid and its derivatives and glycosaminoglycans.

That is, the solid preparation of the present invention contains an active ingredient and a carboxyl group-containing monosaccharide or a derivative thereof. The carboxyl group-containing monosaccharide or derivative thereof may be uronic acid (such as glucuronic acid) or an amide thereof (such as glucuronic acid amide), a salt thereof (such as glucuronic acid salt), or a lactone (such as glucuronolactone). The solid preparation may further contain glycosaminoglycans. Glycosaminoglycans may coexist in contact with the carboxyl group-containing monosaccharide or derivative thereof in the solid preparation, but the group does not come into direct contact with the carboxyl group-containing monosaccharide or derivative thereof. They may coexist by dividing (grouping). For example, a group containing a carboxyl group-containing monosaccharide or a derivative thereof (for example, a pharmaceutical group containing an active ingredient and a carboxyl group-containing monosaccharide or a derivative thereof) and a group containing a glycosaminoglycan (eg, an active ingredient and a glycosyl derivative thereof). It may be contained in a form grouped into a preparation group containing saminoglycans). The weight ratio between the carboxyl group-containing monosaccharide or its derivative and the glycosaminoglycan may be about the former / the latter = 5/95 to 95/5. Type of active ingredient is not particularly limited, vitamins, such as vitamin B ₆ compound may be at least one selected from vitamin B ₁ class and vitamin B ₁₂ compound.

Solid preparation of the present invention may be a formulation comprising vitamin B ₆ compound with a carboxyl group-containing monosaccharide or a derivative thereof, a group comprising vitamin B ₆ compound with a carboxyl group-containing monosaccharide or a derivative thereof, vitamin The preparations may be divided into groups containing B ₁ , vitamin B ₁₂ and glycosaminoglycans. For example, solid preparation comprises a vitamin B ₆ compound, glucuronic acid or its amides, and granules group including its salt or glucuronolactone, and vitamin B ₁ class and vitamin B ₁₂ compound and chondroitin sulfate or a salt thereof And a granulated powder group. Furthermore, the solid preparation of the present invention may be substantially free of glucosamines. The solid preparation may contain a disintegrating agent, but exhibits a high disintegrating property even if it contains substantially no disintegrating agent. The solid preparation may be a coated preparation, for example, a coated tablet.

The present invention also includes a method for producing a solid preparation by granulating an active ingredient and a carboxyl group-containing monosaccharide or a derivative thereof or tableting the granulated product. In this method, a granulated powder group including vitamin B ₆ compound with a carboxyl group-containing monosaccharide or a derivative thereof, a granulated powder group including a vitamin B ₁ class and vitamin B ₁₂ compound and glycosaminoglycans The mixture containing the mixture may be compressed to produce a solid preparation.

  Furthermore, the present invention also includes a method for improving the disintegration property of a solid preparation containing an active ingredient and a carrier, wherein the disintegration property of the solid preparation is improved by using a carboxyl group-containing monosaccharide or a derivative thereof as a carrier. . In this method, the disintegrability of the solid preparation may be improved by combining (or using in combination) a carboxyl group-containing monosaccharide or a derivative thereof and a glycosaminoglycan.

  In the present specification, “carboxyl group-containing monosaccharide or derivative thereof” may be simply referred to as “carboxyl group-containing sugar component”. The monosaccharide lactone means a cyclic ester compound in which a carboxyl group and a hydroxyl group form an ester bond in the molecule.

  “Grouping” means a means or form for suppressing direct contact of a plurality of components. Usually, a plurality of components are intervening components (inactive pharmaceutical ingredients) such as a carrier component and a coating component of a preparation. Are separated and formulated into a formulation (formulation by grouping).

  In this invention, since it contains a carboxyl group-containing sugar component, the disintegration property of a solid preparation (such as a vitamin preparation) can be improved without using a disintegrant. Moreover, the disintegration property of the solid preparation can be further improved by the combined use with glycosaminoglycans. Furthermore, the grouping of the carboxyl group-containing sugar component and the glycosaminoglycans can improve disintegration, can effectively prevent coloring, and can provide a solid preparation excellent in stability (storage stability). Furthermore, in the vitamin preparation, there is no coloring and the stability of the active ingredient can be improved, and the content of the active ingredient is not reduced.

  The solid preparation of the present invention contains a carboxyl group-containing sugar component in order to improve disintegration. The “monosaccharide” of the carboxyl group-containing monosaccharide may be an aldose such as glucose, mannose, galactose, xylose, and the like. “Monosaccharide” is usually glucose. Examples of the carboxyl group-containing monosaccharide include sugar acids (for example, polyoxydicarboxylic acids such as aldanoic acid and glycanoic acid), uronic acids (for example, alduronic acids such as glucuronic acid, mannuronic acid, galacturonic acid (formyl group or carbonyl group) Examples thereof include polyoxycarboxylic acids having a carboxyl group)) and aldonic acids (for example, polyoxycarboxylic acids such as D-gluconic acid). Examples of derivatives of carboxyl group-containing monosaccharides include amides (sugar amides; uronic acid amides such as glucuronic acid amides; aldonic acid amides such as gluconic acid amides), salts (metal salts such as sodium and potassium, etc.) Alkaline metal salts, alkaline earth metal salts such as magnesium, calcium, etc .; ammonium salts; amine salts, etc., esters or acyclic esters (methyl esters, ethyl esters, propyl esters, isopropyl esters, butyl esters, t-butyl esters, etc.) Lactones that are cyclic esters, mono- or dilactones of sugar acids; glucuronolactones such as δ-D-glucuronolactone and γ-D-glucuronolactone, uronolactones such as mannuronic acid lactone and galactonolactone (Or Uron); aldonolactone such as δ-D-gluconolactone and γ-D-gluconolactone). These components can be used alone or in combination of two or more.

Among these carboxyl group-containing sugar components, aldonic acids (gluconic acids, such as gluconic acid, gluconic acid amide, gluconate, gluconic acid ester, gluconolactone, etc.) and uronic acids (alduronic acid (eg, glucuronic acid) ), Alduronic acid amide (for example, glucuronic acid amide), glucuronic acid salt, glucuronic acid ester, uron (for example, glucuronolactone) and the like are preferable. In particular, uronic acids, especially glucuronic acids (for example, at least one selected from glucuronic acid, glucuronic acid amide, glucuronic acid salt, glucuronic acid C _1-6 alkyl ester, and glucuronolactone) are often used.

  The carboxyl group-containing sugar component may be synthesized or a commercially available product (for example, glucuronolactone can be obtained from Sumitomo Chemical Co., Ltd.) may be used as it is. In addition, the carboxyl group-containing sugar component is pulverized by a pulverizer such as a hammer mill, and has an appropriate particle size, for example, an average particle size of 5-1000 μm, preferably 10-500 μm (for example, 15-200 μm), more preferably 20 You may adjust and use about ~ 100micrometer (for example, 20-80micrometer).

The amount of the carboxyl group-containing sugar component can be selected from a range of about 0.01 to 10,000 parts by weight (for example, 0.1 to 5000 parts by weight) with respect to 1 part by weight of the active ingredient depending on the type of the active ingredient. Usually, 1-1000 parts by weight (for example, 3-500 parts by weight), preferably 5-300 parts by weight (for example, 6-100 parts by weight), more preferably 7-70 parts by weight (for example, 8-50 parts by weight). Part) degree. When the active ingredient is vitamins, the amount of the carboxyl group-containing sugar component is usually 0.1 to 2000 parts by weight (for example, 0.5 to 1000 parts by weight) with respect to 1 part by weight of vitamin B ₁ , for example. for preferably 1 to 500 parts by weight (e.g., 1 to 200 parts by weight), more preferably 2 to 20 parts by weight (e.g., 5 to 15 parts by weight), vitamin _{B 6} compound 1 part by weight, usually 1 500 parts by weight (eg 1 to 300 parts by weight), preferably 2 to 200 parts by weight (eg 4 to 150 parts by weight), more preferably 10 to 100 parts by weight (eg 30 to 70 parts by weight), vitamin B against ₁₂ such 1 part by weight, usually 50 to 1,500,000 parts by weight (e.g., 100 to 1,000,000 parts by weight), preferably 1,000 to 100,000 parts by weight (e.g., 5,000 to 50,000 parts by weight) More preferably from 10,000 to 20,000 parts by weight (e.g., 12,000 to 18,000 parts by weight) may be about. In addition, the usage-amount of the carboxyl group-containing sugar component with respect to the total amount of vitamins can be selected from the ratio with respect to the said active ingredient.

  When such a carboxyl group-containing sugar component is used, the disintegration property of the solid preparation can be greatly improved. In order to further improve disintegration, it is preferable to combine a carboxyl group-containing sugar component and glycosaminoglycans. When such components are combined, high disintegration can be obtained even if the disintegrant is substantially not contained. Examples of the glycosaminoglycans include hyaluronic acid or a salt thereof (alkali metal salt such as sodium hyaluronate), chondroitin or chondroitin sulfate or a salt thereof (alkali metal salt such as sodium or potassium salt, alkali such as calcium salt). Earth metal salts, etc.), heparin, heparan sulfate or salts thereof (alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium salts, and the like). These glycosaminoglycans can be used alone or in combination of two or more.

  Preferred glycosaminoglycans are hyaluronic acid or a salt thereof (such as sodium hyaluronate), chondroitin sulfate or a salt thereof (such as sodium chondroitin sulfate), particularly chondroitin sulfate or a salt thereof.

The amount of glycosaminoglycans used is 0.1 to 1000 parts by weight (for example, 1 to 500 parts by weight), preferably 2 to 300 parts by weight, based on 1 part by weight of the active ingredient depending on the type of active ingredient. (For example, 3 to 200 parts by weight), more preferably about 5 to 100 parts by weight (for example, 6 to 50 parts by weight). When the active ingredient is vitamins, the amount of glycosaminoglycans used is, for example, 0.1 to 1500 parts by weight (eg 0.5 to 1000 parts by weight), preferably 1 part by weight of vitamin B ₁ 1 to 500 parts by weight (for example, 2 to 200 parts by weight), more preferably 5 to 50 parts by weight (for example, 6 to 15 parts by weight), and 0.1 to 1000 parts by weight with respect to 1 part by weight of vitamin B ₆ Parts (for example, 0.5 to 500 parts by weight), preferably 1 to 300 parts by weight (for example, 5 to 200 parts by weight), more preferably 10 to 100 parts by weight (for example, 20 to 60 parts by weight), vitamin B 50-1200000 parts by weight to ₁₂ such 1 part by weight (e.g., 100 to 1,000,000 parts by weight), preferably 500 to 100000 parts by weight (e.g., 1,000 to 50,000 parts by weight), more preferred Ku is 5000 to 20000 parts by weight (e.g., 10,000 to 16,000 parts by weight) may be about. In addition, the usage-amount of glycosaminoglycans with respect to the total amount of vitamins can be selected from the ratio with respect to the said active ingredient.

  The weight ratio of the carboxyl group-containing sugar component and the glycosaminoglycan can be selected from the range of the former / the latter = 5/95 to 95/5 (for example, 10/90 to 90/10). In many cases, it is about 85 to 85/15. The weight ratio between the carboxyl group-containing sugar component and the glycosaminoglycans is the former / the latter = 35/65 to 75/25 (for example, 40/60 to 70/30), preferably 45/55 to 65 / About 35 (for example, 50/50 to 60/40) may be sufficient.

  In addition, when a carboxyl group-containing sugar component (for example, glucuronolactone or the like) and glycosaminoglycans are used in combination, the solid preparation may discolor over time and the preparation quality and stability over time may be reduced. Moreover, the usage-amount of these components is usually comparatively large. In such a case, in order to suppress contact between the carboxyl group-containing sugar component and the glycosaminoglycans, the solid preparation is divided into a plurality of these components, that is, a group containing the carboxyl group-containing sugar component, It is preferable to contain in the form grouped into the group containing saminoglycans. The form of grouping is not particularly limited as long as the plurality of components are separated by intervening or separating components and direct contact is suppressed, and for example, powdery, granular (for example, granular) form, layered form It may be. The grouping can usually be performed by formulating at least one of a plurality of components with a carrier component (eg, granulation by granulation, etc.) and / or coating, and the other components are in powder form, etc. It may be a form. In general, a group of preparations in which a carboxyl group-containing sugar component is formulated with a carrier component and a group of preparations in which glycosaminoglycans are formulated with a carrier component are often formed and grouped. In addition, a solid preparation containing a relatively large amount of glycosaminoglycans (such as sodium chondroitin sulfate) expands due to moisture absorption, and the solid preparation (tablet or the like) may be cracked or deformed to reduce storage stability. Even in such a case, if the glycosaminoglycans (such as sodium chondroitin sulfate) are grouped in the form of granules by granulation or the like, cracking and deformation of the solid preparation can be effectively prevented.

  In such a grouping form, the active ingredient only needs to be contained in at least one group, and both groups may contain the same or different active ingredients. For example, the solid preparation is separated into a group containing one or more first active ingredients and a carboxyl group-containing sugar ingredient, and a group containing one or more second active ingredients and glycosaminoglycans. And may be contained in a grouped form. Such grouping is suitable for preparations containing a plurality of active ingredients (for example, repellent ingredients) that are discolored or colored by direct contact or deactivated, and the content of discoloration or coloring and active ingredients A preparation having no decrease and high storage stability can be obtained.

  A carboxyl group-containing sugar component (for example, glucuronolactone and the like) and glycosaminoglycans can function as a carrier component of a solid preparation, particularly as a disintegrant, and can also function as an excipient.

  The preparation of the present invention may contain a conventional carrier component as long as the stability and the like are not impaired. In a solid preparation, at least one of an excipient, a binder, and a disintegrant is usually used as a carrier component or additive in many cases. Examples of excipients include sugar alcohols such as D-mannitol, D-sorbitol, erythritol, and xylitol, sugars such as lactose, glucose, fructose, sucrose, and powdered reduced maltose water candy, crystalline cellulose, powdered cellulose, potato starch, Corn starch, dextrin, β-cyclodextrin, carmellose sodium, light anhydrous silicic acid, hydrous silicon dioxide, silicon dioxide, precipitated calcium carbonate, anhydrous calcium hydrogen phosphate, magnesium oxide, titanium oxide, calcium lactate, aluminate metasilicate Examples thereof include magnesium, synthetic hydrotalcite, talc, and kaolin. Examples of the binder include cellulose derivatives such as methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, crystalline cellulose, polyvinyl alcohol, polyvinyl pyrrolidone (povidone), vinyl pyrrolidone copolymer (copolyvidone), Examples include acrylic polymer, gelatin, gum arabic, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol alginate, sucrose, and the like. Examples of the disintegrant include carmellose, carboxymethylcellulose calcium (carmellose calcium), croscarmellose sodium, low-substituted hydroxypropylcellulose (L-HPC), crospovidone, corn starch, hydroxypropyl starch, partially pregelatinized starch, Examples include alginic acid and bentonite.

  Other carrier components or additives include lubricants (stearic acid, magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, glycerin fatty acid ester, hydrogenated oil, polyethylene glycol, dimethylpolysiloxane, beeswax, white beeswax, etc. ); Antioxidants (dibutylhydroxytoluene (BHT), propyl gallate, butylhydroxyanisole (BHA), tocopherol, citric acid, etc.); preservatives (paraoxybenzoates, etc.); coloring agents (turmeric extract, riboflavin) , Carotene solution, tar pigments, caramel, titanium oxide, bengara, etc.); flavoring agents (sweeteners such as aspartame, ascorbic acid, stevia, menthol, licorice crude extract, simple syrup, etc.); surfactants (polyoxyethylene) Castor oil, glyceryl monostearate, sorbitan fatty acid esters (such as sorbitan monostearate and sorbitan monolaurate), polyoxyethylene polyoxypropylene, polysorbates, sodium lauryl sulfate, macrogol, sucrose fatty acid esters, etc.) Agent (light anhydrous silicic acid, talc, hydrous silicon dioxide, etc.); plasticizer (triethyl citrate, polyethylene glycol, triacetin, cetanol, etc.); sweetener (sucrose, mannitol, D-sorbitol, xylitol, aspartame, etc.) Or synthetic sweeteners); flavoring agents (such as menthol); adsorbents, preservatives, wetting agents, antistatic agents and the like. If reduced maltose (powdered reduced maltose water candy) is used as an excipient, the hygroscopic property is low, so even if glycosaminoglycans are included, deformation and cracking of solid preparations can be prevented, and moldability is also improved. it can.

  Since the solid preparation containing the above components is highly disintegratable, a disintegrant is not necessarily required and may not be substantially contained, but if necessary, a disintegrant (crospovidone, croscarmellose sodium, etc.) is included. Also good. The amount of the disintegrant used can be selected from the range of about 0 to 20% by weight with respect to the total formulation components (total amount of the active ingredient and the carrier component) excluding the coating agent. It may be about 5 to 12% by weight, more preferably about 1 to 10% by weight (for example, 3 to 6% by weight).

  Furthermore, the solid preparation of the present invention may contain glucosamines (glucosamine or a salt thereof such as glucosamine hydrochloride) as long as the preparation characteristics such as disintegration are not impaired. Often not. The content of glucosamines may be in the range of about 0 to 100 parts by weight (preferably 0 to 50 parts by weight, particularly 0 to 20 parts by weight) with respect to 100 parts by weight of the carboxyl group-containing sugar component.

  The type of the active ingredient is not particularly limited, and various physiologically active ingredients and / or pharmacologically active ingredients can be used. Active ingredients include, for example, vitamins, sleep sedatives, antipruritics, antipyretics, analgesics, anti-inflammatory drugs, stomachic medicines, digestives, antacids, antiemetics, antitussives, expectorants, antiasthmatics, constipation Therapeutic, Diarrhea, Hyperlipidemia, Antianginal, Antihypertensive, Hypotension, Anti-arteriosclerosis, Antiobesity, Heart failure, Myocardial infarction, Antiarrhythmic, Diabetes Therapeutic agent, peptic ulcer therapeutic agent, liver disease therapeutic agent, thyroid disease therapeutic agent, hyperuricemia therapeutic agent, rheumatic therapeutic agent, antibiotic, antidepressant, antiallergic agent, antituberculous drug, prostatic hypertrophy therapeutic agent , Osteoporosis therapeutic agents, Alzheimer's disease therapeutic agents, caffeine, minerals, herbal medicines and the like.

The carboxyl group-containing sugar component may act as an active component depending on the type. In such a case, an active ingredient related to the activity of a carboxyl group-containing sugar component (for example, glucuronic acid or its amide, a salt thereof or glucuronic acid such as glucuronolactone) or a glycosaminoglycan (such as sodium chondroitin sulfate) is added. It is advantageous to use. Such active ingredients include vitamins. The vitamins may be either water-soluble vitamins or fat-soluble vitamins. Vitamins are vitamin B ₁ class, often it is at least one selected from vitamin B ₆ compound and vitamin B ₁₂ compound.

The vitamin B ₁ class, such as vitamin B ₁ class (thiamine or a salt thereof, e.g., thiamine hydrochloride, thiamine mononitrate, nitrate Bisuchiamin, thiamine disulfide, etc. thiamine dicetyl sulfate ester salts), vitamin B ₁ derivatives (fursultiamine , Dicetiamine, octothiamine, chicotiamine, bisbutiamine, bisbenchamine, benfotiamine, prosultiamine and other thiamine derivatives or their inorganic acid salts (hydrochloric acid, nitric acid, phosphoric acid salts, such as fursultiamine hydrochloride , etc. hydrochloric dicethiamine) can be exemplified. these vitamins B ₁ class may be used singly or in combination.

Examples of vitamin B ₆ include pyridoxines such as pyridoxine and pyridoxal or salts thereof (hydrochlorides such as pyridoxine hydrochloride, corresponding acetates, phosphates such as pyridoxal phosphate, etc.) and the like. These vitamins B ₆ compounds may be used singly or in combination.

The vitamin B ₁₂ include, for example, mecobalamin, cyanocobalamin, hydroxocobalamin, and cobalamin compound and its salts such as methylcobalamin (hydrochloride, such as hydrochloric acid hydroxocobalamin, such as acetic acid salts such as acetate hydroxocobalamin) can be exemplified. These vitamin B ₁₂ types can also be used alone or in combination of two or more.

Vitamins include vitamin B ₂ (riboflavins such as flavin adenine dinucleotide sodium, riboflavin, sodium riboflavin phosphate, and riboflavin butyrate), vitamin C (ascorbic acid, sodium ascorbate, potassium ascorbate, ascorbic acid) Calcium), vitamin A (retinol acetate, retinol palmitate, vitamin A oil, etc.), vitamin D (ergocalciferol, cholecalciferol, etc.), vitamin E (liver oil, strong liver oil, d-α-tocopherol, dl-α-tocopherol, d-α-tocopherol succinate, dl-α-tocopherol calcium succinate, d-α-tocopherol acetate, dl-α-tocopherol acetate, etc.), nicotinic acids (nicotinic acid, nicotine) Acid amides), vitamin K, pantothenic acids (panthenol, pantothenic acid or salts thereof (calcium pantothenate, etc.)), biotin, folic acid, γ-oryzanol, orotic acid, ioquinin and the like.

These vitamins can also be used alone or in combination of two or more, and may be a complex vitamin preparation. Complex vitamin preparations include, for example, vitamin B ₁ B ₆ B ₁₂ combination preparation, vitamin B ₁ B ₂ B ₆ B ₁₂ combination preparation, vitamin B ₂ B ₆ combination preparation, vitamin B ₂ B ₆ / nicotinic acid / pantothenic acid combination preparation Vitamin B ₁ B ₂ B ₆ C, nicotinic acid, pantothenic acid combination agent and the like may be used.

In addition, when a several active ingredient discolors or colors by direct contact, or deactivates (content reduction), it is preferable to group into a some active ingredient in order to suppress a direct contact. For example, although vitamin B ₁ and vitamin B ₁₂ coexist, the content does not decrease, but when vitamin B ₆ and vitamin B ₁₂ coexist, the content decreases. Therefore, it is preferable to classify vitamin B ₆ and vitamin B ₁₂ into groups. In addition, when using vitamin B ₁ , vitamin B ₆ , and vitamin B ₁₂ , classify each vitamin group (group of vitamin B ₁ , group of vitamin B ₆ and group of vitamin B ₁₂ ). Alternatively, vitamin B ₁ group may be contained in vitamin B group ₆ and / or vitamin B group ₁₂ . It should be noted that vitamin B ₁ does not change color (color) or decrease in content even when combined with vitamin B ₁₂ . Therefore, vitamin B ₁ type is often contained in vitamin B ₁₂ group.

Vitamin B ₆ is destabilized by formulation. Moreover, as described in Patent Document 5, by combining pyridoxine hydrochloride and glucosamine hydrochloride, pyridoxine hydrochloride is relatively stabilized, but the disintegration property of the solid preparation is reduced as described above. The present invention, by formulating a combination of a vitamin B ₆ compound with carboxyl group-containing sugar component, while maintaining a high disintegration property can be stabilized vitamin B ₆ compound. Furthermore, as described above, the carboxyl group-containing sugar component (for example, glucuronolactone and the like) and the glycosaminoglycan (such as sodium chondroitin sulfate) are preferably grouped. Therefore, when using a carboxyl group-containing sugar component and glycosaminoglycans as a carrier component, and using vitamin B ₆ and other vitamins (vitamin B ₁ and / or vitamin B ₁₂ ) as vitamins, A group (for example, granulated or granulated powder group) containing vitamin B ₆ and a carboxyl group-containing sugar component (for example, glucuronic acid (glucuronic acid or its amide, salt or glucuronolactone), etc.), and vitamin B Separating into a group (for example, granulated or sized powder group) containing Class ₁ and / or Vitamin B ₁₂ and glycosaminoglycans (chondroitin sulfate or a salt thereof such as sodium chondroitin sulfate) preferable.

Carboxyl group-containing sugar components (for example, glucuronic acid (glucuronic acid or its amide, its salt or glucuronolactone)), glycosaminoglycans (chondroitin sulfate or its salt, for example, chondroitin sulfate sodium), vitamins B ₆ compounds, solid preparation containing vitamin B ₁ class and / or vitamin B ₁₂ compounds are useful in the prevention and / or treatment of joint disorders (such as joint pain).

  The dosage form of the solid preparation of the present invention is not particularly limited, and may be, for example, powder, fine granules or granules, pills, tablets (bare tablets, film coated tablets), capsules, film coating agents, , Granules, tablets and capsules, preferably film coating agents (film-coated fine granules or granules, especially film-coated tablets).

  The solid preparation of the present invention can be produced by a conventional method. An active ingredient and a carrier component (a carrier component containing a carboxyl group-containing sugar component, etc.) may be mixed to prepare a powder. Usually, the active ingredient and the carrier component are granulated, and if necessary, a granulated product is prepared. A granule (fine granule or granule) is prepared by granulation, or a bare tablet can be prepared by tableting a mixture containing a granulated product (particularly, a mixture of the granulated product and a carrier component). Capsules can be prepared by filling capsules with the granules.

  Granulation can be performed by a conventional method such as a stirring granulation method, a fluidized bed granulation method, an extrusion granulation method, or a dry granulation method. A preferred granulation method is a fluidized bed granulation method. In granulation, the active ingredient and the carrier component are often granulated using a solution containing a binder. For example, by spraying a solution containing the binder on the fluidized bed of the active ingredient and the carrier component. Can be granulated.

  Grouping with solid preparations is a formulation (for example, granulation by granulation, etc.) and / or coating of at least one of a plurality of ingredients (for example, repelling ingredients) that cause discoloration or content reduction with a carrier ingredient The other components may be in the form of a powder or the like. In a preferred embodiment, a formulation group in which one component is formulated with a carrier component and a formulation group in which the other component is formulated with a carrier component are prepared, and both formulation groups are formulated into one dosage form. Grouped formulations are prepared.

More specifically, the solid preparation of the present invention comprises a granulated powder group containing a carboxyl group-containing sugar component (for example, a granule or a sized powder powder group) and a granulated powder group containing a glycosaminoglycan (for example, , Granules or granulated powder group), and at least one granulated powder group containing active ingredients (vitamins, etc.). The solid preparation containing both of the granulated powder groups may be a powder or a granule, or may be a tablet obtained by tableting a mixture of both the granulated powder groups and, if necessary, a carrier component. . In a particularly preferred embodiment, a granulated powder group containing vitamin B ₆ and a carboxyl group-containing sugar component, and a solid powder containing a granulated powder group containing vitamin B ₁ , vitamin B ₁₂ , and glycosaminoglycans. Tablets can be obtained by tableting a preparation, for example, a mixture containing both of the above granulated powders, and optionally mixed with a carrier component. In addition, when a preparation (tablet or the like) containing glycosaminoglycans (such as sodium chondroitin sulfate) is stored under high humidity, the preparation may absorb moisture and swell to cause the preparation to crack. In such a case, a glycosaminoglycan (such as sodium chondroitin sulfate) is granulated and mixed with a component containing a carboxyl group-containing sugar component in the form of a granulated product (such as granules or granulated powder). In this case, cracking and deformation of a solid preparation (tablet etc.) can be effectively prevented even when stored under high humidity (for example, under low temperature and high humidity).

  As described above, the solid preparation of the present invention may be a coated preparation coated with a coating base, for example, a coated tablet. Coating bases include hydroxypropylmethylcellulose (hypromellose), hydroxypropylcellulose, methylcellulose, povidone, copolyvidone, polyvinyl alcohol, polyvinyl alcohol copolymers, water soluble bases such as macrogol, water insoluble bases such as ethyl cellulose, hydroxy Enteric bases such as propylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, cellulose acetate phthalate, hydroxypropylmethylcellulose acetate succinate, methacrylic acid copolymer, acrylic acid copolymer, carboxyvinyl polymer, polyvinyl acetal diethylaminoacetate, Aminoalkyl methacrylate copolymers, Gastric base such as polyvinyl acetate diethylamino acetate, gum arabic, pullulan, carnauba wax, shellac, macrogols, glycerol fatty acid ester, such as magnesium stearate can be exemplified. These coating bases can be used alone or in combination of two or more. The coating layer may be formed in one layer or a plurality of layers. Preferred coating bases are hydroxypropyl methylcellulose and polyvinyl pyrrolidone polymers (povidone, copolyvidone, etc.).

  The coating agent may further contain additives such as a filler, a lubricant, a masking agent, a plasticizer, and a colorant as necessary. Additives include talc, precipitated calcium carbonate, magnesium stearate, calcium stearate, titanium oxide, macrogol 6000, copolyvidone, triacetin, triethyl citrate, glycerin, propylene glycol, riboflavin, yellow ferric oxide, ferric oxide, yellow For example, No. 5 aluminum lake. These additives can be used alone or in combination of two or more.

  As the lubricant added to the coating agent, talc is preferable from the viewpoint of the temporal stability of the appearance. The content of the additive (such as talc) is usually 1 to 30% by weight (for example, 3 to 25% by weight), preferably 5 to 20% by weight (for example, 10 to 15) in the coating agent in terms of solid content. % By weight).

  The coating amount is 1% by weight or more (for example, 1 to 50% by weight), preferably 2 to 20% by weight (for example, 3 to 18% by weight), based on an uncoated preparation (elementary granule, uncoated tablet, etc.), Preferably it is about 5 to 15 weight% (for example, 6 to 12 weight%).

  The coating preparation can be obtained by spraying a coating agent containing a coating base onto an uncoated preparation (elementary granule, plain tablet, etc.) using a film coating machine.

  The present invention also proposes a method for improving the disintegration property of a solid preparation. That is, since the preparation of the present invention contains a carboxyl group-containing sugar component as a carrier, the disintegration property of the solid preparation can be improved. Furthermore, when the carboxyl group-containing sugar component and glycosaminoglycans are contained in combination, the disintegration property of the solid preparation can be further improved. Therefore, the solid preparation of the present invention may contain a disintegrating agent, but does not necessarily contain a disintegrating agent.

The content of the active ingredient can be selected from the range of about 0.01 to 80% by weight, usually 0.1 to 50% by weight, preferably 1 depending on the type of the active ingredient. It may be about ˜30% by weight. The dose of the active ingredient can be selected according to the degree of symptoms, age, sex, route of administration, etc., and is 0.01 to 500 mg, preferably 0.1 to 300 mg (for example, 0.5 to 250 mg) per day. More preferably, it may be about 1 to 200 mg (for example, 5 to 150 mg). In the vitamin preparation, the unit dosage of vitamin B ₁ type is, for example, 1 to 300 mg (for example, 50 to 200 mg, preferably 75 to 150 mg), and the unit dosage of vitamin B ₆ type is 1 to 100 mg (for example, 5 -50 mg, preferably 10-30 mg), and the unit dose of vitamin B ₁₂ is about 0.001-2 mg (for example, 0.01-0.5 mg, preferably 0.03-0.1 mg) Also good. The solid preparation of the present invention can be administered once or divided into a plurality of times (for example, 2 to 6 times) per day.

  The present invention is effective in improving the disintegration property of a solid preparation, is effective in preventing discoloration (coloring) and content reduction, and enhancing storage stability. Therefore, the solid preparation of the present invention is suitable for oral administration and is useful as an oral administration preparation.

  Hereinafter, the present invention will be described in more detail based on examples, but the present invention is not limited to these examples.

Example 1
To a fluidized bed granulator (FD-3S type, Pauleck Co., Ltd.), 218.32 g of fursultiamine hydrochloride, 1600 g of sodium chondroitin sulfate, 419.56 g of powdered reduced maltose water candy, and a 0.04 wt% cyanocobalamin solution were added. After spraying 300 g, 600 g of an 8 wt% hydroxypropylcellulose aqueous solution was sprayed and granulated, followed by pulverization (Power Mill, Showa Chemical Machinery Co., Ltd.) to obtain a T group sized powder. Next, 40 g of pyridoxine hydrochloride and glucuronolactone (a pulverized product obtained by pulverizing a commercial product to an average particle size of about 20 to 80 μm, the same applies hereinafter) and powder were added to a fluidized bed granulator (FD-3S type, Pauleck Co., Ltd.) 142 g of reduced maltose water candy was added, and 850 g of an aqueous solution of 8% by weight hydroxypropylcellulose was sprayed for granulation, followed by pulverization (Power Mill, Showa Chemical Machinery Co., Ltd.) to obtain Group B sized powder. Crospovidone (162 g) and magnesium stearate (21.6 g) were added to and mixed with 2057.4 g of Group T sized powder and 2025 g of Group B sized powder, and the resulting mixed powder was milled using a rotary tableting machine with a diameter of 9.5 mm. The tablets were made with an R-face punch having a locality radius of 8 mm to obtain plain tablets (weight 395 mg per tablet, thickness 5.5 mm).

  Using a coating solution in which 3500 g of the above undissolved tablets were dissolved and suspended in 360 g of hydroxypropylmethylcellulose (TC-5MW), 45 g of talc, 45 g of titanium oxide, and 0.938 g of yellow iron sesquioxide in 4050 g of purified water, 500 type, Paulek) was coated at 10% by weight based on the weight of the uncoated tablet to obtain film-coated tablets.

Example 2
In the same manner as in Example 1, T group sized powder was obtained. Next, 40 g of pyridoxine hydrochloride and 2000 g of glucuronolactone were added to a fluidized bed granulator (FD-3S type, Pauleck Co., Ltd.), and 316 g of powdered reduced maltose water candy was sprayed, and 925 g of an 8 wt% hydroxypropylcellulose aqueous solution was sprayed. After granulation, it was pulverized (Power Mill, Showa Chemical Machinery Co., Ltd.) to obtain Group B sized powder. Magnesium stearate 21.6 g was added to and mixed with 2057.4 g of Group T sized powder and 2187 g of Group B sized powder, and mixed and mixed in the same manner as in Example 1 to obtain uncoated tablets and film-coated tablets.

Example 3
In a fluidized bed granulator (FD-5S type, Pauleck Co., Ltd.), 215.52 g of fursultiamine hydrochloride, 40 g of pyridoxine hydrochloride, 1600 g of sodium chondroitin sulfate, 2000 g of glucuronolactone and 561.56 g of powdered reduced maltose water candy In addition, after spraying 300 g of 0.04 wt% aqueous cyanocobalamin solution. After spraying 1450 g of an aqueous solution of 8% by weight hydroxypropylcellulose, the mixture was granulated and then pulverized (Power Mill, Showa Chemical Machinery Co., Ltd.) to obtain a sized powder. Crospovidone (162 g) and magnesium stearate (21.6 g) were added to and mixed with 4082.4 g of the sized powder, and then uncoated tablets and film-coated tablets were obtained in the same manner as in Example 1.

Example 4
After adding 1091.6 g of fursultiamine hydrochloride and 1277.8 g of powdered reduced maltose water candy to a fluidized bed granulator (FD-3S type, Pauleck Co., Ltd.), and spraying 375 g of a 0.16 wt% aqueous cyanocobalamin solution, After spraying 1000 g of an aqueous solution of 8% by weight hydroxypropylcellulose and granulating, it was pulverized (Power Mill, Showa Chemical Machinery Co., Ltd.) to obtain T group sized powder. Next, 40 g of pyridoxine hydrochloride, 2000 g of glucuronolactone, and 142 g of powdered reduced maltose water candy are added to a fluidized bed granulator (FD-3S type, Pauleck Co., Ltd.), and 850 g of an 8 wt% hydroxypropylcellulose aqueous solution is sprayed. After granulation, it was pulverized (Power Mill, Showa Chemical Machinery Co., Ltd.) to obtain Group B sized powder. A method similar to that of Example 1 was added to 441 g of Group T sized powder and 2025 g of Group B sized powder, 1440 g of sodium chondroitin sulfate, 162 g of crospovidone, 21.6 g of magnesium stearate and 176.4 g of powdered reduced maltose water candy. To obtain uncoated tablets and film-coated tablets.

Example 5
To the T group sized powder 2057.4g and the B group sized powder 2025g obtained in the same manner as in Example 1, 162 g of croscarmellose sodium and 21.6 g of magnesium stearate were added and mixed. An uncoated tablet and a film-coated tablet were obtained in the same manner as in Example 1 except that tableting was performed with a rotary tableting machine.

Comparative Example 1
In the preparation of Group B sized powder of Example 1, 2000 g of glucosamine hydrochloride was used instead of 2000 g of glucuronolactone, and 2057.4 g of T group sized powder obtained in the same manner as in Example 1 and Group B sized powder. In the same manner as in Example 1, except that 162 g of croscarmellose sodium and 21.6 g of magnesium stearate were added to and mixed with 2025 g of powder, and the resulting mixed powder was tableted with a rotary tableting machine. Coated tablets were obtained.

Test example 1
The uncoated tablet was stored in a glass bottle sealed at 50 ° C. for 2 months, and then the appearance change was examined. In addition, the color of the uncoated tablet used for the test is a light pink color. The film-coated tablets were stored sealed in a glass bottle at 60 ° C. for 2 weeks and at 60 ° C. for 4 weeks, and then the pyridoxine hydrochloride content was measured and calculated as the residual rate.

Test example 2
The film-coated tablets (20 tablets each) were opened and stored in a glass bottle for 2 weeks at a temperature of 5 ° C. and a relative humidity of 88%, and the percentage of broken tablets was expressed as a percentage.

Test example 3 (disintegration)
The disintegration property of the film-coated tablet was tested in accordance with the fast-acting tablet according to the disintegration test method (general test method Japanese Pharmacopoeia 15th revision).

  The results are shown in the table together with the formulation.

  From the table, disintegration can be greatly improved by using glucuronolactone (Example 1 and Example 2) as compared with glucosamine hydrochloride (Comparative Example 1). Moreover, the formulation (Example 1 and Example 5) using crospovidone and croscarmellose sodium as the disintegrant and the formulation not containing the disintegrant (Example 2) showed high disintegration properties.

  Furthermore, in the preparations grouped into a granulated product of pyridoxine hydrochloride and glucuronolactone and a granulated product of other components, the appearance change of the preparation can be prevented and pyridoxine hydrochloride can be stabilized. Further, by blending sodium chondroitin sulfate in the form of a granulated product, the tablet can be prevented from cracking during storage at low temperature and high humidity.

Claims (14)

  A solid preparation comprising an active ingredient and a carboxyl group-containing monosaccharide or a derivative thereof.   The solid preparation according to claim 1, wherein the active ingredient is vitamins. Vitamin B ₆ compound and a carboxyl group-containing mono- or solid preparation according to claim 1 or 2, wherein and a derivative thereof.   The solid preparation according to any one of claims 1 to 3, wherein the carboxyl group-containing monosaccharide or a derivative thereof is uronic acid, an amide thereof, a salt thereof, or a lactone.   The solid preparation according to any one of claims 1 to 4, wherein the carboxyl group-containing monosaccharide or a derivative thereof is at least one selected from glucuronic acid or an amide thereof, a salt thereof, and glucuronolactone.   Furthermore, the solid formulation in any one of Claims 1-5 containing glycosaminoglycan.   The solid preparation according to claim 6, which is divided into a group containing a carboxyl group-containing monosaccharide or a derivative thereof and a group containing glycosaminoglycans. Active ingredient, solid preparation according to claim 1, vitamin B ₆ such, is at least one selected from vitamin B ₁ class and vitamin B ₁₂ compound. 9. A group comprising vitamin B ₆ and a carboxyl group-containing monosaccharide or a derivative thereof, and a group comprising vitamin B ₁ and vitamin B ₁₂ and glycosaminoglycans. The solid formulation in any one of. And vitamin B ₆ compound, glucuronic acid or its amides, and granules group including its salt or glucuronolactone, a granulated powder group including a vitamin B ₁ class and vitamin B ₁₂ compound and chondroitin sulfate or a salt thereof The solid formulation in any one of Claims 1-9 containing.   A method of producing a solid preparation by granulating an active ingredient and a carboxyl group-containing monosaccharide or a derivative thereof, or tableting the granulated product. Striking the granules group including vitamin B ₆ compound with a carboxyl group-containing monosaccharide or its derivative, a mixture comprising a granulated powder group including a vitamin B ₁ class and vitamin B ₁₂ compound and glycosaminoglycans The method according to claim 11, wherein the solid preparation is produced by tableting.   A method for improving the disintegrability of a solid preparation comprising an active ingredient and a carrier, wherein the disintegration of the solid preparation is improved by using a carboxyl group-containing monosaccharide or a derivative thereof as a carrier.   The method according to claim 13, wherein the disintegration property of the solid preparation is improved by combining a carboxyl group-containing monosaccharide or a derivative thereof and glycosaminoglycans.